The duocarmycins are potent antitumour agents with potential in the development of antibody drug conjugates (ADCs) as well as being clinical candidates in their own right. The duocarmycin family of natural products incorporates the parent molecule duocarmycin SA (FIG. 1, (1)), several naturally occurring analogues and the extended and sandwiched compounds CC-10653 (FIG. 1, (2)) and yatakemycin (FIG. 1, (3)). The mode of action of these compounds, involving reversible alkylation of the N3 of adenine through shape dependant activation on binding to the minor groove of DNA, has been the subject of extensive investigation and has led to the design and synthesis of numerous analogues. Most recently, research has focussed on prodrugs that are reductively or oxidatively-activated or that carry glycosidic linkages. This desire to generate prodrug structures is due to the ultrapotent activity of the drug molecules.
One route into the design of new molecular entities with therapeutic potential whilst minimising cytotoxicity is via tumour cell targeting, rather than prodrug design. Antibody-drug conjugates, in which the antibody targets a highly cytotoxic molecule to the tumour site of action, have met with some recent success in the clinic.